A reproducible large animal model without the disadvantages imposed by implantation of carcinogens or heterotransplants would enhance investigation of the biology and treatment of infiltrative, intrinsic glial tumors. Radiation has been implicated in the development of primary CNS tumors in humans and animal models. We describe the development of glioblastoma multiforme (GBM) in 5 or 11 rhesus monkeys 0.5-4.5 years after 3500 cGY whole brain radiation. Eleven monkeys were treated with fractionated whole brain radiation (350 cGY/day for 10 days). We obtained non- and contrast-enhanced MRIs before treatment and serially after treatment. Animals were sacrificed when they developed neurological symptoms or parenchymal lesions on MRI; 5 animals are alive without MRI abnormalities. One animal developed neurological symptoms 2.5 years after radiation but had no evidence of radiographic or microscopic disease. Five animals developed GBM which appears as contrast-enhancing masses on MRI after six months (N=1), 2y (N=2 and 4Y (N=2). Three animals survived for 0.5, 2 and 3 years after development of MRI abnormalities. The lesions were supratentorial (N=3), infratentorial (N=1) and in both compartments (N=1). Three animals had diffuse and bilateral lesions. Four animals had multifocal tumors on histopathological analysis. All tumors demonstrated hypercellularity with giant cells, nuclear pleomorphism, mitoses, neovascularity, necrosis, and pseudopalisading. Extensive infiltration occurred along white matter tracts and along Virchow-Robin spaces. This infiltrative glioma model, which has histopathological characteristics identical to gliomas in humans, will be useful for investigation of the anatomy and mechanism of tumor infiltration, for genetic analysis of tumor progression, and for examining new treatments for infiltrative glial tumors.